Additionally, patients with Gaucher disease Type 1 and carriers of the disease have an increased risk for developing Parkinson’s disease (see neuropsychological disorders).3,4 Consequently, genetic counsellors and healthcare professionals will also be faced with the decision of whether to discuss the risk of Parkinson’s disease with patients who have Gaucher disease or who are carriers of the disease, and if so, at what time point (see support and counselling for Gaucher disease).5,6
What is carrier testing for Gaucher disease?
Carrier testing aims to identify couples who are at risk of having children with a serious autosomal recessive disease. Carrier couples are offered genetic consultations to discuss their reproductive options, where prenatal diagnosis is explained.7 The Ashkenazi Jewish population have an increased risk for a number of autosomal recessive diseases, including Gaucher disease.8-10The carrier frequency of Gaucher disease has been reported as 1 in 17 in individuals of Ashkenazi Jewish ethnicity in Israel.11 Similarly, within the New York metropolitan area, the carrier frequency of Gaucher disease among individuals of Ashkenazi Jewish ethnicity has been reported as 1 in 15.2.12
Who performs carrier testing for Gaucher disease?
The screening practices of healthcare providers for Gaucher disease in North America was determined in one study. A total of 1454 prenatal healthcare providers (midwives, n=795; physicians, n=450; genetic counsellors, n=209) participated in the study. Jewish ancestry-based disease-carrier screening for couples in which one or both partners were Jewish was currently offered by the majority of genetic counsellors (99.5%), physicians (92.2%) and midwives (79.7%). In this study, of those providers who offered Jewish ancestry-based disease-carrier screening for Gaucher disease, it was always or sometimes offered by most genetic counsellors (95.6%) and physicians (84.8%) but was never offered by 56.3% of midwives. These data highlighted that Jewish ancestory-based disease-carrier screening was offered at a high rate, and more may need to be done to provide Gaucher disease-carrier screening services.13
The availability of carrier testing for Gaucher disease varies worldwide; more information is provided on the Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/conditions/C0017205/).
Outcomes of carrier testing and prenatal screening for Gaucher disease in the Ashkenazi Jewish population in Israel
In Israel, referral to carrier screening programmes is routine for couples and women of Ashkenazi Jewish descent who are pregnant or planning a pregnancy to determine the risk of having affected children. In order to assess the various aspects of this screening programme, a nationwide study on the outcomes of clinical Gaucher disease carrier screening performed at all Israeli genetic centres between January 1, 1995 and March 31, 2003 was conducted by Zuckerman et al. JAMA 2007.14
Prior to carrier testing, all participants received an information brochure that included an explanation of autosomal recessive inheritance, the natural history, carrier frequency and test sensitivity of the screened diseases (at the time the study was conducted, this consisted of Bloom syndrome, Canavan disease, cystic fibrosis, Fanconi anaemia, familial dysautonomia, fragile X syndrome, Gaucher disease and Tay-Sachs). The option for prenatal diagnosis was also included in the information brochure. The variable expression of Gaucher disease was included in each information brochure; enzyme replacement therapy was mentioned in 3 out of 10 information brochures. In 74% of cases, a genetic counsellor was also available to provide more detailed information. Across these centres, testing was performed using a two-step sequential process where one partner was tested first, and a second test was offered only if the first partner was identified as a carrier. Each centre tested for four GBA1 mutations (N370S [c.1226A>G; p.Asp409Ser], 84GG [c.84dupG; p.Leu29AlafsTer18], L444P [c.1448T>C; p.Leu483Pro] and IVS2+1 [c.115+1G>A]).14
The estimated total number of persons screened across 10 of the 12 genetic centres was 28,893 during the study period, and approximately 1660 carriers were identified. A total of 83 carrier couples were reported; follow-up information was available for 66 couples, and 65 couples were interviewed. Of these 132 participants, sociodemographic data were available for 127 participants; 89% were of full Ashkenazi Jewish ethnicity. Most couples (53/65) were at risk for having children with mild or asymptomatic Gaucher disease Type 1; however, one couple was identified as at risk of having children with severe Gaucher disease Type 2 or Type 3. Post-screening, 95% (62/65) of interviewed couples received genetic counselling in-person at the screening centre, with 9 out of 10 centres routinely referring couples for medical consultation at the Israel Gaucher Disease Referral Centre. During this medical consultation, the reproductive risk for Gaucher disease, predicted disease severity based on the couple’s genotypes, and available therapy were all discussed.14
Of the 65 couples who were at risk for having children with Gaucher disease Type 1, all couples had ≥1 pregnancy during the study period, resulting in a total of 90 pregnancies (one pregnancy, 66%; two pregnancies, 29%; three pregnancies, 5%). For the couple at risk for having children with severe Gaucher disease Type 2 or Type 3, a pregnancy did not occur during the study period. For 76% of pregnancies (68/90), a prenatal diagnosis procedure was performed, which was more common in pregnancies at risk of moderate disease (15/17) than those at risk of mild or asymptomatic disease (53/73). Foetuses with Gaucher disease Type 1 were diagnosed in 16 of 68 pregnancies at risk (predicted mild or asymptomatic disease, n=13; predicted moderate disease, n=3). Of these 16 pregnancies, four were terminated (predicted mild or asymptomatic disease [N370S/N370S], n=2; predicted moderate disease, n=2 [N370S/84GG, n=1; L444P/R496H (c.1604G>A; p.Arg535His), n=1]). There were significantly fewer pregnancy terminations in couples who received medical counselling with a Gaucher disease expert in addition to genetic counselling (1/13 vs 3/3 with no medical counselling; p=0.007).14
A prenatal diagnosis procedure was not performed for 33 children who were born to ‘at risk’ couples (born before the parents knew they were at risk, n=22; born after the parents were identified as carriers of Gaucher disease, n=11). Sixteen couples had already had children before learning their carrier status and 12 couples decided not to test their older children for Gaucher disease. Among the four couples who did have their older children tested, 4/8 children were homozygous for the N370S (c.1226A>G; p.Asp409Ser) mutation. Nine children were born after prenatal diagnosis (N370S/N370S, n=8; N370S/IVS2+1 [c.115+1G>A], n=1). At the time of interview, these 13 children were between 12 days and 19 years old (mean age, 5.6 years); three additional children were not yet born. None of these children required enzyme replacement therapy or were ever hospitalised; all untested children were reportedly asymptomatic according to their parents, except for two siblings of unknown genotype with anaemia.14
In this study, Gaucher disease testing among most couples of Ashkenazi Jewish ethnicity in Israel did not result in termination of affected pregnancies; however, prenatal screening did result in a few pregnancy terminations. It is suggested that the main possible benefit of carrier testing allows ‘at risk’ couples to be identified and make an informed choice.14
Attitudes of couples identified as at risk for having children with Gaucher disease Type 1 through carrier testing
As part of a nationwide study conducted in Israel to evaluate the outcomes of carrier testing for Gaucher disease, the experiences of 65 couples identified as at risk for having an affected child were assessed. The pre-test information was regarded as insufficient but the information for post-result counselling was deemed better. Approximately 70% of participants felt that the genetic counselling was directive, and mostly towards prenatal diagnosis and against pregnancy termination. Attitudes towards pregnancy termination correlated with participant genotype, with the perception of Gaucher disease severity and also with attendance at additional medical consultation. Thirty participants were at risk of having an affected child and 80% came to terms with their decision to utilise prenatal diagnosis; of the few who terminated the pregnancy, many regretted their decision. It was determined that, overall, most participants did not regret having been carrier-tested, and supported the continuation of carrier testing individuals of Ashkenazi Jewish ethnicity. It is suggested that extensive genetic and medical counselling be offered for any future carrier testing, especially for low-penetrance, manageable diseases like Gaucher disease.15
A New York screening programme for lysosomal storage diseases in 65,605 newborns: results for Gaucher disease
Initiated in May 2013, five ethnically diverse New York City hospitals conducted a pilot newborn screening for Fabry disease, Gaucher disease, Niemann Pick A/B, mucopolysaccharidosis type 1 and Pompe disease, to determine the suitability of these lysosomal storage diseases for public health mandated screening. Following consent from postpartum parents, 65,605 infants were screened over 4 years using dried blood spot testing. Screen-positive infants underwent confirmatory enzymology, DNA testing and biomarker quantitation when available. A total of 69 infants were identified as screen-positive; 23 were confirmed true positives and were predicted to have late-onset phenotypes, six of whom currently had undetermined disease status. There were 17 screen-positives for Gaucher disease, indicating a referral rate of 0.026%. Overall, these data suggest that newborn screening for lysosomal storage diseases is more likely to detect those at risk for late-onset disease; affected infants are being followed for clinical management and long-term outcome.16